Process for the preparation of 3-(3-chloro-1h-pyrazol-1-yl)pyridine

ABSTRACT

3-(3-Chloro-1H-pyrazol-1-yl)pyridine is prepared by coupling 3-bromopyridine with commercially available 3-aminopyrazole, purifying the 3-(3-amino-1H-pyrazol-1-yl)pyridine by crystallization, and converting the amino group to a chloro group by a Sandmeyer reaction.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of the following U.S. ProvisionalPatent Applications: Ser. No. 62/031,557-filed Jul. 31, 2014, the entiredisclosure of which is hereby expressly incorporated by reference intothis Application.

BACKGROUND

The present invention concerns an improved process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine.

US 20130288893(A1) describes, inter alia, certain(3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amides and carbamates and theiruse as pesticides. The route to prepare such compounds involved thepreparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine by the directcoupling of 3-bromopyridine with 3-chloropyrazole. The 3-chloropyrazolewas prepared by a) treating 1H-pyrazole with 2-dimethylsulfamoylchloride and sodium hydride to provideN,N-dimethyl-1H-pyrazole-1-sulfonamide, b) treating theN,N-dimethyl-1H-pyrazole-l-sulfonamide with perchloroethane and n-butyllithium to provide 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide, andc) removing the N,N-dimethylsulfonamide from3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide with trifluoroaceticacid to give the 3-chloropyrazole.

The disclosed process produces low yields, relies on a starting materialthat is difficult to prepare (3-chloropyrazole) and provides a productthat is difficult to isolate in a pure form. It would be desirable tohave a process for preparing 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)that avoids these problems.

SUMMARY

The present invention provides such an alternative by coupling3-bromopyridine with commercially available 3-aminopyrazole, purifyingthe 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) by crystallization, andconverting the amino group to a chloro group by a Sandmeyer reaction.Thus, the present invention concerns a process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b),

-   which comprises    -   a) treating 3-bromopyridine

-   with 3-aminopyrazole

-   in a water-miscible polar aprotic organic solvent at a temperature    of about 75° C. to about 155° C. in the presence of a catalytic    amount of copper(I) chloride and a base to provide    3-(3-amino-1H-pyrazol-1-yl)pyridine (8a)

b) crystallizing the 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) fromwater;

c) treating the 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) in aqueoushydrochloric acid with sodium nitrite at a temperature of about 0° C. toabout 25° C. to provide the diazonium salt (8b)

and

d) treating the diazonium salt (8b) with copper chloride at atemperature of about 0° C. to about 25° C.

DETAILED DESCRIPTION

The present invention provides an improved process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) by coupling 3-bromopyridinewith commercially available 3-aminopyrazole, purifying the3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) by crystallization, andconverting the amino group to a chloro group by a Sandmeyer reaction.

In the first step, 3-bromopyridine is coupled with 3-aminopyrazole in awater-miscible polar aprotic organic solvent at a temperature of about75° C. to about 155° C. in the presence of a catalytic amount of copperchloride and a base to provide 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a).While stoichiometric amounts of 3-bromopyridine and 3-aminopyrazole arerequired, it is often convenient to use an excess of 3-aminopyrazole. Anexcess from about 10 mole percent to about 50 mole percent3-aminopyrazole is preferred. The coupling is run in the presence ofabout 5 mole percent to about 50 mole percent copper chloride,preferably from about 15 mole percent to about 30 mole percent copperchloride. The copper chloride may be either copper(I) chloride orcopper(II) chloride. The coupling is also run in the presence of a base.While stoichiometric amounts of 3-bromopyridine and base are required,it is often convenient to use about a 1.5 fold to about a 2 fold excessof base. Alkali metal carbonates are preferred bases. The coupling isperformed in a water-miscible polar aprotic organic solvent. Polaraprotic organic solvents that are soluble in water include nitriles suchas acetonitrile, sulfoxides such as dimethyl sulfoxide, and amides suchas N-methylpyrrolidinone, N,N-dimethylformamide, andN,N-dimethylacetamide. N,N-Dimethylformamide is particularly preferred.

In a typical reaction, copper(I) chloride, 3-aminopyrazole, potassiumcarbonate and N,N-dimethylformamide are introduced into a reactionvessel under a nitrogen atmosphere and 3-bromopyridine is graduallyadded. The mixture is heated at about 110° C. until most of the3-bromopyridine has reacted. The mixture is allowed to cool and most ofthe solvent is removed under reduced pressure. The crude3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) is conveniently isolated andpurified by crystallization from water.

The purified 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) is then convertedto the desired 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) by treatment inaqueous hydrochloric acid with sodium nitrite at a temperature of about0° C. to about 25° C. to provide a diazonium salt followed by treatmentof the diazonium salt with copper chloride at a temperature of about 0°C. to about 25° C. While stoichiometric amounts of reagents arerequired, it is often convenient to use an excesses of reagents withrespect to the 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a). Thus, aqueoushydrochloric acid is used in large excess as the reaction medium. Sodiumnitrite is used in about a 1.5 fold to about a 2 fold excess. Copperchloride is used in about 5 mole percent to about 50 mole percentexcess, preferably from about 15 mole percent to about 30 mole percentexcess. The copper chloride may be either copper(I) chloride, copper(II)chloride or copper powder. To suppress foaming during the reaction awater-immiscible organic solvent such as toluene or chloroform can beadded during the treatment of the diazonium salt with copper chloride.

In a typical reaction, a mixture of 3-(3-amino-1H-pyrazol-1-yl)pyridine(8a) and aqueous hydrochloric acid are mixed and cooled to about 0° C.An aqueous solution of sodium nitrite is slowly added maintaining thetemperature below about 5° C. The suspension is stirred at about 0° C.for about 2 hours. In a separate vessel, a mixture of copper(I) chlorideand toluene are cooled to about 0° C. and the chilled suspension ofdiazonium salt is added at a rate maintaining the temperature belowabout 5° C. The mixture is allowed to warm to about ambient temperature.After completion of the reaction, the mixture is treated with aqueoussodium hydroxide to adjust the pH to about 8 to about 10. The resultingsolution is extracted with a water-immiscible organic solvent. Afterremoval of the solvent, the 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)can be used directly in the next step, or further purified by standardtechniques such as flash column chromatography or crystallization.

The following examples are presented to illustrate the invention.

EXAMPLES 1. Preparation of 3 -(3 - amino-1H-pyrazol-1-yl)p yridine (8a)

A 4-neck round bottomed flask (500 mL) was charged with copper(I)chloride (2.51 g, 25.3 mmol), 1H-pyrazol-3-amine (15.8 g, 190 mmol),potassium carbonate (35.0 g, 253 mmol), and N,N-dimethylformamide (100mL). The mixture was stirred under nitrogen for 10 minutes and3-bromopyridine (12.2 mL, 127 mmol) was added. The mixture was heated at110° C. for 18 hours, at which point HPLC analysis indicated that ˜15.5%3-bromopyridine remained. The reaction was allowed to cool to 20° C. andconcentrated to give a brown residue. Water (200 mL) was added and theresulting suspension was stirred at 20° C. for 2 hours and filtered. Thesolid was rinsed with water (2×50 mL) and dried to afford a pale greensolid. The solid was suspended in water (200 mL) and the resultingsuspension was heated at 90° C. for 2 hours and was filtered hot througha Celite® pad. The pad was rinsed with hot water (50 mL). The combinedfiltrates were allowed to cool to 20° C. to afford a yellow suspension,which was stirred at 20° C. for 2 hours and filtered. The solid wasrinsed with water (2×50 mL) and air dried to afford the desired productas a light yellow crystalline solid (11.6 g, 57%): mp 169-172° C.; ¹HNMR (400 MHz, DMSO-d₆) δ 9.07-8.82 (m, 1H), 8.33 (dd, J=4.6, 1.5 Hz,1H), 8.24 (d, J=2.6 Hz, 1H), 8.00 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.42(ddd, J=8.5, 4.6, 0.8 Hz, 1H), 5.80 (d, J=2.6 Hz, 1H), 5.21 (s, 2H); ¹³CNMR (101 MHz, DMSO-d₆) δ 157.67, 144.68, 138.00, 136.22, 128.30, 123.95,123.17, 97.08; ESIMS m/z 161 ([M+H]⁺).

2. Preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)

To a 3-neck round bottomed flask (100 mL) was charged3-(3-amino-1H-pyrazol-1-yl)pyridine (0.500 g, 3.12 mmol) andhydrochloric acid (37 wt %, 3 mL). The mixture was cooled to 0° C. and asolution of sodium nitrite (0.431 g, 6.24 mmol) in water (3 mL) wasadded in portions at <5° C. The resulting yellow suspension was stirredat 0° C. for 2 hours. To a separate 3-neck round bottomed flask (100 mL)was charged copper(I) chloride (0.371 g, 3.75 mmol) and toluene (3 mL).It was cooled to 0° C. and the yellow suspension was added in portionsat <5° C. The resulting mixture was allowed to warm to 20° C. andstirred for 18 hours. It was basified with 50% sodium hydroxide to pH 10and extracted with ethyl acetate (2×20 mL). The organic layers wereconcentrated to dryness and the residue was purified by flash columnchromatography using 0-10% ethyl acetate/hexanes as eluent. Thefractions containing the desired product were concentrated to give thetitle compound as a white solid (0.340 g, 61%): mp 104-106° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H),8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34(M, 1H), 6.45 (d, J=2.6 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 148.01,142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.08; EIMS m/z 179([M]⁺).

1-4. (canceled)
 5. A process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)

comprising a) treating 3-bromopyridine with 3-aminopyrazole with3-aminopyrazole in the presence of copper chloride and a base.
 6. Theprocess of claim 5, further comprising b) crystallizing the3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) from water.
 7. The process ofclaim 5, wherein the treating is carried out in the presence of awater-miscible polar aprotic organic solvent.
 8. The process of claim 7,wherein the water-miscible polar aprotic organic solvent is selectedfrom the group consisting of acetonitrile, dimethyl sulfoxide,N-methylpyrrolidinone, N,N-dimethylformamide, and N,N-dimethylacetamide.9. The process of claim 7, wherein the water-miscible polar aproticorganic solvent is N,N-dimethylacetamide.
 10. The process of claim 5,wherein the copper chloride is copper (I) chloride or copper (II)chloride.
 11. The process of claim 5, wherein the copper chloride iscopper (I) chloride.
 12. The process of claim 5, wherein the copperchloride is in an amount of from about 5 mole percent to 50 molepercent.
 13. The process of claim 5, wherein the copper chloride is inan amount of from about 15 mole percent to 30 mole percent.
 14. Theprocess of claim 11, wherein the copper (I) chloride is in an amount offrom about 15 mole percent to 30 mole percent.
 15. The process of claim5, wherein the 3-aminopyrazole is in an excess of about 10 mole percentto about 50 mole percent.
 16. The process of claim 5, wherein the baseis an alkali metal carbonate.
 17. The process of claim 16, wherein thebase in an excess of about 1.5 fold to about 2 fold.
 18. The process ofclaim 16, wherein the alkali metal carbonate is potassium carbonate. 19.The process of claim 5, wherein the treating is carried out at atemperature of about 75° C. to about 155° C.
 20. The process of claim17, wherein the copper chloride is in an amount of from about 15 molepercent to 30 mole percent, the 3-aminopyrazole is in an excess of about10 mole percent to about 50 mole percent, and the treating is carriedout at a temperature of about 75° C. to about 155° C.